Fatty acids are one of the most extensively studied classes of compounds due to their important role in biological systems (1,2). Hundreds of different fatty acids exist in nature. They consist of saturated, monounsaturated and polyunsaturated fatty acids, having chain lengths from 4 to 22 carbon atoms. Polyunsaturated fatty acids (PUFAS) contain 16 to 22 carbon atoms with two or more methylene-interrupted double bonds. The PUFA, arachidonic acid, contains 20 carbons and four methylene-interrupted cis-double bonds commencing six carbons from the terminal methyl group, which therefore leads to an abbreviated nomenclature of 20:4 (n-6).
PUFAs can be divided into four families, based on the parent fatty acids from which they are derived: linoleic acid (18:2 n-6), α-linolenic acid (18:3 n-3), oleic acid (18:1 n-9) and palmitoleic acid (16:1 n-7). The n-6 and n-3 PUFAs cannot be synthesised by mammals and are known as essential fatty acids (EFAs). They are required by mammalian bodies indirectly through desaturation or elongation of linoleic and α-linolenic acids, which must be supplied in the diet.
EFAs have a variety of biological activities. For instance, it has been suggested that they can play an important role in modulating cystic fibrosis(3). Intake of n-3 PUFAs has been found to be associated with a reduced incidence of coronary arterial diseases, and various mechanisms by which n-3 PUFAs act have been proposed.[4,5] Some n-3 and n-6 PUFAs also possess antimalarial [6] or anti-inflammatory properties.[7] Furthermore, one of the EFAs' most important biological roles is to supply precursors for the production of bioactive fatty acid metabolites that can modulate many immune functions.[8]
Arachidonic acid (AA) is the most extensively studied of the EFAs and it is a principal precursor for many important biological mediators. There are two pathways for arachidonic acid metabolism (1) the cycloxygenase pathway which leads to the formation of prostaglandins and thromboxanes, and (2) the lipoxygenase pathway which is responsible for the generation of leukotrienes and lipoxins. These metabolites, collectively called eicosanoids, have been implicated in the pathology of a variety of diseases such as asthma[9] and other inflammatory disorders.[10,11]
Although EFAs play important roles in the biological process of the mammalian body; they are not widely used as therapeutics due to their limited availability in vivo. They are readily degradable by β-oxidation, which is the major oxidative pathway in fatty acid metabolism. The net process of β-oxidation is characterised by the degradation of the fatty acid carbon chain by two carbon atoms with the concomitant production of equimolar amounts of acetyl-coenzyme A.
To overcome the problem of β-oxidation, some work has been done to design and synthesise modified PUFAS, such as the β-oxa and β-thia PUFAs[12,13]. These compounds were shown to have enhanced resistance to β-oxidation while still retaining certain biological activities of the native PUFAs.
The present invention relates to the design and preparation of another group of modified PUFAS, the nitro analogues of PUFAS. The rationale was that the nitro group is chemically similar to COOH group with regard to size, charge and shape. In addition, the nitro compounds are a group of relatively stable compounds and are resistant to β-oxidation by preventing CoA thioester production, which is the first step in β-oxidation of fatty acids. This also means that the nitro compounds will not be incorporated into lipids and will more likely be present in a free form.